Bronchial asthma is a chronic inflammatory disease of airways showing respiratory stenosis, in which symptoms such as paroxysmal dyspnea, stridor, cough, etc. are observed. Many cells such as bronchial epithelial cells, mast cells, eosinophils, T lymphocytes, etc. are involved in its onset and development. One of the most important characteristics of bronchial asthma is that airways are hyperresponsive to irritants (airway hyperresponsiveness). This airway hyperresponsiveness is attributable to airway inflammation caused mainly due to exfoliation of bronchial epithelial cells by neurotransmitters secreted from the cells such as eosinophils, etc., infiltrated into airways, and it is also considered that genetic factors or environmental factors will affect the airway hyperresponsiveness complicatedly.
When the inflammatory reaction of airways is triggered by external irritants (allergens, exhausts) or viral infection, adhesion molecules including VCAM-1, ICAM-1 and the like are expressed on bronchial epithelial cells or on capillary endothelial cells around the bronchi [J. Allergy Clin. Immunol., 96, 941 (1995)] to produce cytokines or chemotactic substances. In patients with bronchial asthma, the function of Th2 type helper T cells is activated to increase the production of Th2 type cytokines such as IL-3, IL-4, IL-5, IL-13, GM-CSF, etc., or chemokines such as eotaxin, RANTES, etc. IL-4 or IL-13 has an activity of inducing IgE production, and IL-3 or IL-4 has an activity of inducing the growth of mast cells. Furthermore, eosinophils differentiate and proliferate in response to IL-5, GM-CSF, etc. and infiltrate into the airways in response to eotaxin or RANTES [Allergy Asthma Proc., 20, 141 (1999)].
Epithelial cells that cover the bronchial mucosa not only have the barrier function to prevent direct transmittance of external irritants to submucosal tissues and the function to excrete mucus secretions or foreign matters, but also regulate bronchoconstriction by secreted epithelium-derived smooth muscle relaxing factors, etc. Eosinophils infiltrated into the airways of patient with bronchial asthma release through degranulation of intracellular granule proteins such as activated MBP (major basic protein), ECP (eosinophil cationic protein), etc. [Compr. Ther., 20, 651 (1994)]. By the cytotoxic action of these granular proteins, the exfoliation and damages of epithelial cells occur. The exfoliation of epithelial cells leads to exposure of sensory nerve terminals, increase in epithelial permeability and loss of epithelium-derived smooth muscle relaxing factors. Also, leukotriene C4 (LTC4) or platelet activating factor (PAF) produced by eosinophils increase tension of bronchial smooth muscle. It is considered that when the foregoing changes are repeated to make it chronic, the bronchial walls would be thickened to cause airway hyperresponsiveness.
As stated above, it is known that genes of the cytokines or adhesion molecules described above are increasingly expressed, accompanied by inflammation of the airways, but there is no report to systematically analyze the change of genes, expression of which are localized in the lesion of lung/bronchi and which are associated with the onset of airway hyperresponsiveness.
On the other hand, chitinase activity was detected in blood plasma from patient with Gaucher's disease [J. Clin. Invest., 93, 1288 (1994)), the protein was purified as only one chitinase in mammal [J. Biol. Chem., 270, 2198 (1995)] and the gene was cloned [J. Biol. Chem., 270, 26252 (1995)]. This chitinase has been used as a disease marker but no relationship between bronchial asthma and chitinase has not been reported.
The present invention provides a novel protein, expression of which increases in the lung/bronchi having increased airway hyperresponsiveness, or salts thereof, its partial peptide or salts thereof, its signal peptide; a DNA encoding the protein, its partial peptide or signal peptide; recombinant vectors; transformants; methods of manufacturing the protein; pharmaceutical compositions comprising the protein or DNA; antibodies against the protein; methods for screening compounds that suppress or promote the expression of the protein; methods for screening compounds that suppress or promote the activity of the protein; compounds obtainable by the screening methods; etc.